This invention relates to novel compounds, pharmaceutical compositions and a method of inhibiting the 5-lipoxygenase pathway of arachidonic acid metabolism in an animal in need thereof which comprises administering to such animal an effective, 5-lipoxygenase inhibiting amount of a 4,5-diaryl-2(substituted) imidazole or a pharmaceutically acceptable salt thereof.
Lombardino et al., U.S. Pat. No. 3,772,441, issued Nov. 13, 1973 disclose compounds of the formula ##STR1## and the pharmaceutically acceptable acid addition salts thereof, Ar and Ar.sup.1 are each selected from furyl, thienyl, pyridyl, phenyl and substituted phenyl, wherein said substituents are selected from fluoro, chloro, bromo, and C.sub.1-4 alkoxy;
R.sup.1 is selected from H or C.sub.1-4 alkyl; and PA1 R.sup.2 is selected from trifluoro methyl, C.sub.1-4 alkyl, furyl, thienyl, pyridyl, and substituted phenyl wherein said substituents are selected from fluoro, chloro, bromo, or C.sub.1-4 alkoxy. Lombardino et al. disclose that such compounds are antiinflammatory agents based on their activity in the carrageenan rat foot adena test. Such test is useful for detecting compounds which are cyclooxygenase inhibitors, but is of no known utility in detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway. Lombardino et al. also state that compounds are useful as antiarthritic agents but there is no further statement as to how such antiarthritic activity was determined. Such a blanket statement of antiarthritic activlity does not disclose that such compounds have 5-lipoxygenase pathway inhibition. PA1 R.sub.1 is C.sub.1-6 alkyl or polyhalo C.sub.1-6 alkyl; PA1 R.sub.2 and R.sub.3 are independently selected from monosubstituted phenyl wherein said substituent is selected from C.sub.1-4 alkoxy, chloro or fluoro. PA1 R.sup.3 is lower alkyl; and PA1 R.sup.4 is lower alkyl. PA1 R.sub.1 is mono or polyhalo C.sub.1-4 alkyl or C.sub.1-4 alkyl; and PA1 R.sub.2 and R.sub.3 are independently selected from mono-substituted phenyl wherein said substituents are selected from C.sub.1-4 alkoxy, chloro or fluoro. PA1 R.sub.1 is C.sub.1-6 alkyl and mono- and polyhalo C.sub.1-4 alkyl; and PA1 R.sub.2 and R.sub.3 are independently selected from monosubstituted phenyl wherein said substituent is selected from C.sub.1-4 alkoxy, Cl or F. Cherkofsky et al. state that such compounds have antiinflammatory activity and analgesic activity as indicated by the adjuvant-induced arthritis assay in rats, which, as stated above, is of no known utility in detecting compounds which are inhibitors of the 5-lipoxygenase pathway. PA1 R.sub.1 is polyfluoro C.sub.1-2 alkyl; PA1 R.sub.2 and R.sub.3 are independently selected from 2-thienyl, 3-thienyl, 3-pyridyl, 2-furyl or monosubstituted phenyl wherein said substituent is selected from C.sub.1-4 alkoxy, Cl or F and PA1 R.sub.4 is H, PA1 R.sup.1 and R.sup.2 are the same or different, but one of which always being pyridyl, are pyridyl or monosubstituted phenyl wherein said substituent is selected from lower alkoxy, chloro, fluoro or bromo. PA1 one of the groups of R.sub.2 and R.sub.3 represents phenyl which is optionally substituted by halo or lower alkoxy and the other is a 6-membered heteroaromatic ring, and salts of such compounds. PA1 R.sub.1 and R.sub.2 are independently selected from pyridyl, thienyl or monosubstituted phenyl wherein said substituent is selected from chloro, fluoro or C.sub.1-4 alkoxy. PA1 R.sup.1 and R are independently selected from pyridyl or monosubstituted phenyl wherein said substituent is selected from halo or C.sub.1-4 alkoxy; and PA1 Y.sup.1 is H or CN; provided that when X.sup.1 is NH.sub.2, Y.sup.1 is CN, and when X.sup.1 is NHCN, Y.sup.1 is H; PA1 n is 0, 1 or 2; PA1 R.sup.2 is selected from H, C.sub.1-6 alkyl, or mono- or polyhalo C.sub.1-4 alkyl; PA1 R and R.sup.1 are independently selected from pyridyl or monosubstituted phenyl wherein said substituent is selected from halo or C.sub.1-4 alkoxy; provided that when R and/or R.sup.1 are pyridyl, R.sup.2 is other than C.sub.1-6 alkyl, tetrahaloethyl or C.sub.1-4 perhaloalkyl; and PA1 Y is H, CN, or C.sub.1-4 alkyl; provided that when X is NH.sub.2, Y is CN and when X is NHCN, Y is H; PA1 R.sup.1 is selected from H or C.sub.1-4 alkyl; and PA1 R.sup.2 is selected from trifluoro methyl, C.sub.1-4 alkyl, furyl, thienyl, pyridyl, and substituted phenyl wherein said substituents are selected from fluoro, chloro, bromo, or C.sub.1-4 alkoxy. PA1 R.sub.1 is C.sub.1-6 alkyl or polyhalo C.sub.1-6 alkyl; and PA1 R.sub.2 and R.sub.3 are independently selected from monosubstituted phenyl wherein said substituent is selected from C.sub.1-4 alkoxy, chloro or fluoro, and pharmaceutically acceptable salts thereof. PA1 R.sup.3 is H or lower alkyl; and PA1 R.sup.4 is lower alkyl; PA1 R.sub.1 is mono or polyhalo C.sub.1-4 alkyl or C.sub.1-4 alkyl; and PA1 R.sub.2 and R.sub.3 are independently selected from mono-substituted phenyl wherein said substituents are selected from C.sub.1-4 alkoxy, chloro or fluoro, and pharmaceutically acceptable salts thereof. PA1 R.sub.1 is C.sub.1-6 alkyl and mono- and polyhalo C.sub.1-4 alkyl; and PA1 R.sub.2 and R.sub.3 are independently selected from mono-substituted phenyl wherein said substituent is selected from C.sub.1-4 alkoxy, Cl or F, and pharmaceutically acceptable salts thereof. PA1 R.sub.1 is polyfluoro C.sub.1-2 alkyl; PA1 R.sub.2 and R.sub.3 are independently selected from 2-thienyl, 3-thienyl, 3-pyridyl, 2-furyl or monosubstituted phenyl wherein said substituent is selected from C.sub.1-4 alkoxy, Cl or F; and PA1 R.sub.4 is H, PA1 R.sup.1 and R.sup.2 are the same or different, but one of which always being pyridyl, are pyridyl or monosubstituted phenyl wherein said substituent is selected from lower alkoxy, chloro, fluoro or bromo.
Lombardino et al., J. Med. Chem. 17(11), 1182-1188(1974) disclose compounds of the formula ##STR2## wherein Ar and Ar.sup.1 are selected from methoxyphenyl, 4-ethoxyphenyl, 2-pyridyl and 4-halophenyl; and R is selected from 4-halophenyl, CF.sub.3, phenyl and 4-methoxyphenyl. Lombardino et al. disclose that some of such compounds have antiinflammatory activity in the carrageenan rat paw edema test which is useful for detecting compounds which are inhibitors of cyclooxygenase but is of no known utility of detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway.
Bender et al., J. Med. Chem., 28, 1169-1177 (1985), disclose compounds of the formula ##STR3## wherein R is methyl or ethyl, R.sup.1 is H, methyl or ethyl, R.sup.2 is 4-methoxyphenyl, and R.sup.3 is 4-methyoxyphenyl, 4-bromophenyl or 3-fluorophenyl. Bender et al. also disclose that some of such compounds have antiarthritic activity in the rat adjuvant-induced arthritis assay and immuno-regulatory activity mouse subliminal oxazolone-induced contact sensitivity assay. The adjuvant-induced arthritis assay is useful for detecting compounds which are cyclooxygenase inhibitors, but is of no known utility for detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway. The mouse subliminal oxazolone induced arthritis assay is useful for detecting compounds which are immunostimulants but is of no known utility for detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway.
Cherkofsky et al., U.S. Pat. No. 4,190,666, issued Feb. 26, 1980 disclose compounds of the formula ##STR4## wherein: n is 0, 1 or 2;
and
Cherkofsky et al. also disclose that such compounds have antiinflammatory activity as determined by the established adjuvant-induced arthritis assay in rats; immunoregulatory effects as determined by the non-established adjuvant-induced arthritis assay in rats; and analgesic activity as determined by the phenylquinone writhing test. As stated above, the established adjuvant-induced arthritis test is of no known utility in detecting or suggesting cmpounds with 5-lipoxygenase pathway inhibiting activity. The non-established adjuvant arthritis assay is useful for detecting compounds with cyclooxygenase inhibiting activity but is of no known utility for detecting or suggesting compounds with 5-lipoxygenase pathway inhibiting activity. The phenylquinone writhing test is useful for detecting compounds with cyclooxygenase inhibiting activity but is of no known utility for detecting or suggesting compounds with 5-lipoxygenase pathway inhibiting activity.
Zauer et al., Chem Ber, 106, 1628-1636(1973), disclose 4,5-bis(p-chlorophenyl)-2-(methylthio)imidazole and 4,5-bis(p-methoxyphenyl)-2-methylimidazole. There is no disclosure in Zaver, et al. regarding any biological activity of such compounds.
Ferrini et al., U.S. Pat. No. 4,308,277, issued Dec. 29, 1981, disclose compounds of the formula ##STR5## wherein: R.sub.1 and R.sub.2 are independently selected from thienyl or mono-substituted phenyl wherein said substituent is selected from lower alkoxy and halo;
Ferrini, et al. state that such compounds have immunoregulatory, antiinflammatory, antithrombolic and/or antinociceptive activity as exhibited by their activity in the Kaoline paw oedema assay in normal rats and adjuvant-induced arthritic assay in rats, the phenyl-p-benzoquinone-induced writhing assay in mice, the iv administered acetic acid induced writing assay in rats, the pulmonary embolism assay in rabbits, and an assay of inhibition of prostaglandin synthesis from arachidonic acid by spermatocystic enzymes in cattle. The Kaolin paw oedema assay is useful for detecting compounds which are cyclooxygenase inhibitors, but is of no known utility in detecting compounds which are inhibitors of the 5-lipoxygenase pathway. As stated above, the phenyl-p-benzoquinone and adjuvant-induced arthritis assays are of no known utility in detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway. The iv-administered acetic acid induced writing assay in rats is useful for detecting compounds which are cyclooxygenase inhibitors. The assay of inhibition of prostaglandin synthesis induced by spermatocystic enzymes is useful for detecting compounds which are inhibitors of the cyclooxygenase pathway. None of the acetic acid induced writhing assay, pulmonary embolism assay or the prostaglandin synthesis assay of any known utility are useful for detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway.
Dupont, Belgium Patent Application No. 845,074, published Nov. 2, 1977, disclose compounds of the formula ##STR6## wherein: n is 0, 1 or 2;
Dupont discloses that such compounds have antiinflammatory and immunoregulatory properties based on their activity in the non-established and established adjuvant-induced arthritis assay in rats, both of which, as stated above, have no known utility in detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway.
Janino et al., Bulletin of the Chemical Society of Japan, 45, 1474-1480 (1972), and White et al., J. Org. Chem., 29, 1926-1930 (1964), disclose 2,4,5-tri(p-chlorophenyl)imidazole. There is no disclose in either reference regarding any biological activity of this compound.
Cherkofsky et al., U.S. Pat. No. 4,182,769, issued Jan. 8, 1980, disclose compounds of the formula ##STR7## wherein: n is 0, 1 or 2;
Ferrini et al., U.S. Pat. No. 4,461,770, issued July 24, 1984, disclose compounds of the formula ##STR8## wherein at least one of the radicals R.sub.1 and R.sub.2 is a substituted or unsubstituted heteroaryl group and the other is a substituted or unsubstituted aryl group; R.sub.3 is H or lower alkyl, n is 0, 1 or 2, and R.sub.4 is substituted or unsubstituted aliphatic hydrocarbon radical, and pharmaceutically usable salts thereof. Ferrini et al. also disclose that such compounds have anti-inflammatory, anti-nociceptive and/or anti-thrombotic activity as well as an inhibitory action on prostaglandin synthesis based on their effects in the Kaolin paw oedema test, the carrageenan paw edema test, the phenyl-p-benzoquinone induced writhing assay in mice; the arachidonate induced embolic assay in rabbit lung and the in vitro inhibition of prostaglandin synthesis from arachidonic acid assay. As stated above, none of such assay systems have any known utility for detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway.
Cherkofsky et al., U.S. Pat. No. 4,159,338, issued June 26, 1979, disclose compounds of the formula ##STR9## wherein: n is 0, 1 or 2;
and pharmaceutically acceptable acid addition salts thereof.
Cherkofsky, et al. also disclose that such compounds have antiinflammatory, antiarthritic and/or analgesic activity based on their activity in the established adjuvant induced arthritis assay in rats and in the phenylquinone writhing test in mice. As stated above, none of such assays are of any known utility in detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway.
Bender et al., U.S. Pat. No. 4,175,127, issued Nov. 20, 1979, disclose compounds of the formula ##STR10## wherein: R.sub.3 is H, C.sub.1-6 alkyl or mono- or polyhalo C.sub.1-4 alkyl; and
Bender, et al. also disclose that when R.sub.3 is H, such compounds are useful only as intermediates, and when R.sub.3 is other than H, such compounds have potent anti-arthritic activity based on their activity in the adjuvant-induced polyarthritis assay in rats which, as stated above, is of no known utility for detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway.
Fitzi et al., U.S. Pat. No. 3,940,486, issued Feb. 24, 1976, and Fitzi et al. U.S. Pat. No. 3,929,807, issued Dec. 30, 1975, disclose compounds of the formula ##STR11## wherein: R.sub.1 is halo-substituted phenyl; and
Fitzi et al. also disclose that such compounds have antiinflammatory, antinociceptive and antipyretic action based on their activity in the Bolus alba oedema test in rats; the phenyl-p-benzoquinone-induced writhing assay in mice, and yeast-induced fever assay in rats. As stated above, such assays have no known utility in detecting or suggesting compounds with 5-lipoxygenase pathway inhibiting activity.
Lantos et al., J. Med. Chem., 27(1), 72-75(1984), disclose 4-(4-methyoxyphenyl)-5-(4-pyridyl)-2-thione-imidazole and 4-(4-fluorophenyl)-5-(4-pyridyl)-2-thione-imidazole as intermediates.
Cherkofsky et al., U.S. Pat. No. 4,199,592, issued Apr. 12, 1980, disclosed compounds of the formula ##STR12## wherein: R.sub.3 is H; and
Cherkofsky, et al. also disclose that such compounds have antiinflammatory, antiarthritic and/or analgesic activity based on their activity in the established adjuvant-induced arthritis assay in rats and the phenylquinone induced writhing assay in mice. As stated above, none of such assays either disclose or suggest comounds with 5-lipoxygenase inhibiting activity.